Diabetes mellitus (DM) is a common endocrine metabolic disease with heredity tendency. It is caused mainly by the absolute or relative hyposecretion of the insulin, and it causes metabolic disturbance of saccharide, fat, protein, and subsequently vitamin, water and electrolyte. The manifestations include the increase of glycemia and urine glucose, and the patients have the symptoms of polydipsia, polyphagia, polyuria, dry mouth, and general weakness. The morbidity rate of diabetes mellitus is 1 to 5%, and shows a trend of gradually increasing. Diabetes mellitus, cancer, and cardiovascular diseases are referred as three worldwide serious diseases. The object of treating diabetes mellitus is to correct the disturbance of carbohydrate metabolism, so as to eliminate the symptoms, promote restoration of the function of pancreatic islet, improve the insulin resistance, maintain the better healthy condition and physical strength, and prevent and treat various complications.
Diabetes mellitus is commonly divided into two types: Insulin Dependent Diabetes Mellitus (type I, IDDM) and Non-Insulin Dependent Diabetes Mellitus (type II, NIDDM). Since the pathogenesis for theses two types of diabetes mellitus are different, the medicaments for treating them are far different, which are stated respectively as follows.
Type I diabetes mellitus is caused by virus infection in hereditarily susceptible person which produces the paradoxical reaction of the islet cells through immunoreactions, so that the pancreatic islets begin to be damaged and even lose their function completely. About 5% of diabetes mellitus is type I. At present, the medicaments for treating type I diabetes mellitus mainly include exogenous insulin (including human insulin and animal insulin), drugs having the insulin-like effect, insulin-like growth factor-1 (IGF-1), novel long-acting insulin preparation, and Jin Qi hypoglycemic tablet, etc.
Type II diabetes mellitus is caused by direct impair of β-islet cells which decrease the secretion of insulin. Most of type II diabetes mellitus is caused by a combination of factors that may include genetic traits, life style, environmental contributors, metabolic disorders, obesity, and so on. In this disease state, muscular, hepatic and adipose tissues are insensitive to the insulin, which thereby decrease the intake of the glucose. Most of diabetics suffer from type II diabetes mellitus. At present, the medicaments for the clinical treatment of NIDDM mainly include sulphonylureases, biguanides, other hypoglycemic drugs and adjuvants, etc.
The sulphonylureas hypoglycemic drugs bind to the receptors on the cell membrane of β-islet cells to close the potassium ion channel thereby blocking flowout of potassium ion and inducing depolarization of the cell membrane, so that the calcium ion channels are opened to allow the extracellular calcium ions flow inwardly. The increase of intracellular calcium ions concentration triggers the release of the insulin. Sulphonylureas hypoglycemic drugs can be divided into two generations according to their time of coming into existence. The first generation includes tolpropamide, and the second generation includes glibenclamide (euglucan), gliclazide (diamicron), glipizide and gliquidone etc.
Biguanide hypoglycemic drugs inhibit appetite, improve the binding of insulin to the receptors, promote the anaerobic glycolysis in cells, inhibit tissue respiration and inhibit hepatic gluconeogenesis. The biguanide hypoglycemic drugs mainly include metformin, phenformin and buformin.
Other hypoglycemic drugs mainly include thiazolidinedione drugs (such as troglitazone, rosiglitazone, and pioglitazone, etc), β3-adrenoceptor regulators, glucagon receptor antagonists, fatty acid metabolism interfering agents, α-glycosidase inhibitors (such as acarbose, voglibose, miglitol), and aldose reductase inhibitors, etc.
Recently, the development of research on glycometabolism related endogenous peptide hormone provides a new idea for the treatment of diabetes mellitus. When human body intakes nutrient materials, the enteroendocrine cells release enteropeptide hormone which mainly includes glucagon like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) and regulate metabolism by affecting the insulin generation, gastrointestinal peristalsis, and islet cell proliferation. Wherein, GLP-1 is secreted by entero-pancreatic cells, and activates the adenylate cyclase to synthesize cA MP by highly specifically binding to the GLP-1 receptor of β-islet cells, so as to further activate the protein kinase. The metabolic signal (glycometabolism) and kinase signal (binding of GLP-1) cooperate on the cell membrane level, which finally cause the Ca2+ channel to open. The inward flowing of the calcium ions further stimulates the secretion of insulin and inhibits the generation of glucagon, thereby decreases the postprandial blood glucose and maintain blood glucose concentration at a constant level. Also, GLP-1 has the function of neuroregulation, and can retard gastric emptying, and inhibit appetite. All of these are greatly beneficial for the control of diabetes mellitus. Normally, GLP-1 stimulates insulin secretion depending on the blood glucose concentration. As the blood glucose concentration decreases, the effect of GLP-1 on stimulating insulin secretion decreases. Therefore, the action of GLP-1 on decreasing blood glucose is self-limited, and cannot cause hypoglycemia. So, for treating diabetes mellitus, the medicaments with the GLP-1-like action are greatly desirable for the treatment of diabetes mellitus. GLP-1R agonists have been one researching focus of the international drug development organizations. At present, the researches on GLP-1 R mainly focus on the polypeptide regulators. For example, AC 2993 of Amylin Corporation has been applied for clinic test in US (IND). AC2993 is a 39-amino acids polypeptide and has the effect of promoting the secretion of insulin as GLP-1. Since the polypeptide drugs are inconvenient for oral administration and are readily to degrade, non-peptide GLP-1 R regulators are the new researching direction at present.